Project Summary Understanding the molecular basis of epigenetic mechanisms that control the transcriptional response of cells to environmental signals is essential to understand how environment, aging and lifestyle impact physiology. My lab has discovered an evolutionarily conserved mechanism of epigenetically inherited transcriptional memory that involves the interaction of genes with nuclear pore proteins (8-10). Using both the INO1 gene from yeast and interferon ?-inducible genes in HeLa cells as models for transcriptional memory, we find that previously expressed genes interact with nuclear pore proteins for 4- 7 generations and this leads to an altered chromatin structure in the promoters of these genes. This allows RNA polymerase II to bind to these promoters, poising them for re-activation. We have now find that the scope of genes regulated by transcriptional memory includes dozens of stress-induced genes in yeast that utilize the same system. Therefore, transcriptional memory is a universal, ancient and conserved mechanism by which cells can integrate previous experience to affect future physiology. The goals of this work are to determine the molecular mechanisms that control establishment and inheritance of transcriptional memory in yeast and human cells.